This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A brief period of TcR stimulation triggers na[unreadable]ve T cells into an IL-2-dependent proliferative program that continues in the absence of further activation through the TcR. In contrast to na[unreadable]ve T cells, memory T cells can be activated either through their TcR or through exposure to innate cytokines such as IL-12 and IL-18 in the absence of antigenic stimulation. This raised the possibility that IL-12 and IL-18 may also program memory T cell proliferation in a form of 'bystander activation', without the need for TcR stimulation. Interestingly, we found that memory CD8+ T cells undergo cytokine-driven "programmed" proliferation in the absence of cognate antigen. In addition, we found that the antigenic and cytokine-exposure history of memory T cells directly influenced their patterns of cytokine expression following restimulation with LCMV peptide. These results indicate that memory CD8+ T cell proliferation and subsequent responsiveness to antigenic restimulation may be subject to differential regulation by recent innate (e.g., IL-12, IL-18) or adaptive (e.g., TcR) stimulation. Current studies are focused on greatly expanding our knowledge of cytokine-mediated T cell activation. For instance, we have tested every murine cytokine that is commercially available in combination with every other murine cytokine (2,000 cytokine combinations) to determine which ones have the capacity to stimulate virus-specific T cells. Our results indicate that there are new, previously uncharacterized combinations of cytokines that can directly activate (or inactivated) CD8+ T cell functions in as little as 6 hours after exposure.